There has been developing interest in using solid dosage forms for administration of pharmaceutically active agents. The majority of solid dosage forms, such as tablets and capsules, are intended for oral administration. Upon ingestion, the tablet disintegrates, the contents of the tablets disperse, and medicament(s) are released in the gastrointestinal (“GI”) tract. The release of the medicaments of the tablets could be rapid or immediate; the release could be delayed for some period after ingestion; or the release could occur in a controlled or sustained manner. Compared to other dosage forms such as suspensions, solutions, or elixers, tablets and capsules tend to have increased robustness, increased stability, and certain manufacturing advantages such as low cost of manufacturing, packaging, and shipping.
Yet, in spite of the advantages of tablet dosage forms, certain limitations still exist. For instance, limitations of tablet dosage forms become evident when tablets are compressed during preparation of the dosage form. The robustness of a compressed tablet can generally be increased by compressing the tablet components with increasing force. However, increasing the tablet compression force tends to adversely affect tablet disintegration properties. Another limitation of the tablets is the breakage of the sustained release or enteric coatings of the active beads or granules during compression.
Capsules are often used to contain beads with sustained release or enteric coatings to avoid these limitation of traditional tablets. However, capsules also have limitations, including loss of aqueous solubility of gelatin capsules due to cross-linking, particularly upon exposure to trace quantities of active aldehydes; gelatin capsules must be protected from extremes of humidity to preserves the desired mechanical properties; capsule filling machines are slower than typical production tablet presses; capsules are most susceptible to tampering; and gelatin capsules are made from animal sources which may be unacceptable to some patient populations for dietary or religious reasons.
There exists a need for tablets with components with sustained release or enteric coatings capable of withstanding breakage during compression.
There have been numerous efforts to overcome the limitations experienced during compression of tablet dosage forms. For example, EP 0 196 546 B1 alleges that the fracture of coated active-containing granules occurring during tablet compression is reduced by including microcrystalline cellulose in the tablet matrix. U.S. Pat. No. 5,780,055 to Habib et al. allegedly provides a method for preparing a crushed tablet comprising compressing active-loaded particles with highly porous freeze-dried cushioning beads. Such cushioning beads are spherical or semi-spherical agglomerates of suitable composition having structural and deformation properties suitable for forming a compressible composition when admixed with suitable proportions of membrane coated active-loaded particles. The reference discloses that the cushioning beads deform preferentially, i.e., they deform at lower pressures than the membrane-coated active beads, to substantially prevent rupture or cracking of the membrane of the active-loaded particles. Generally, cushioning beads, including those described in Habib, do not contain a biologically active substance and are referred to as “placebo millispheres” (see Aulton et al. in 20 Drug Development and Industrial Pharmacy 3094 (1994)) and “cushioning agents” (see Mount et al. in 22 Drug Development and Industrial Pharmacy 612 (1996)).
However, the highly porous cushioning beads are lighter in weight than the active-loaded particles, by virtue of its functionality. The incorporation of these two types of beads with drastically different densities into a tablet presents several problems. First, segregation of the heavier beads from the lighter beads in the hopper is inevitable. Secondly, the homogeneity of the powder blend can not be assured during transport. Thirdly, the unevenly distributed cushioning beads defeats their purpose of protecting the active-loaded particles during compression. As a result, the dose uniformity of the tablets and the integrity of the coatings of the beads become questionable.
There is a need to develop methods for preparing tablet dosage forms incorporating cushioning components which allow greater compressibility of the table components yet overcome the problems presented by incorporating cushioning components with the active pharmaceutical components. In particular, there is a need for methods of preparing tablets such that dose uniformity and integrity of coatings useful for achieving certain release profiles is maintained.
Another limitation of tablets arises from the need to incorporate a large quantity of biologically active ingredient(s) into a tablet can often result in tablets of such a large size that administration is unsuitable for geriatric and pediatric patients, or certain patients who already have difficulty in swallowing solid medications. Oral solutions such as liquid suspension dosage forms have been developed as an alternative to tablets in order to circumvent this problem; however, many challenges are encountered by a pharmaceutical scientist in the development of a suspension. Suspensions are often thermodynamically unstable and may result in aggregation and sedimentation during storage. Problems are often encountered because the accuracy of the dose depends on the even distribution of particles in the suspensions at the time the preparations are administered to the patients.
Accordingly, it is often desirable to have a tablet that disintegrates and disperses rapidly in the mouth without requiring any water intake other than the normal flow of saliva. Such tablets are easier for the elderly and children who often have difficulty in chewing or swallowing large capsules or tablets; they are convenient to use since the patient may not have convenient access to water for swallowing conventional dosage forms; and they may be particularly convenient dosage forms for delivering larger drug doses for any patient, because fast-disperse tablets are never swallowed whole. Thus, even large doses of drug that would otherwise require excessively large single tablets or capsules or the administration of multiple tablets or capsules at one time may be conveniently administered in a single rapid-disperse tablet that does not need to be swallowed whole. This overcomes one of the limitations of tablets containing a large quantity of biologically active ingredient(s), where the resulting large size tablets are often unsuitable for administration to geriatric and pediatric patients, or certain patients who have difficulty in swallowing solid medications.
Accordingly, there remains a need to formulate a rapidly disintegrating tablet which disperses in a liquid to form a ready-to-use suspension in order to overcome a number of the challenges by combining the advantages of both tablets and suspensions and circumventing their shortcomings.
U.S. Pat. No. 6,221,392 to Khankari et al. discloses a fast-dissolving tablet utilizing a rapidly dissolvable filler and a relatively high level of lubricant.
U.S. Pat. No. 5,223,264 Wehling et al., U.S. Pat. No. 5,639,475 to Bettman et al. and U.S. Pat. No. 5,807,577 to Ouali disclose fast-disintegrating tablets utilizing an effervescent material to promote disintegration.
A rapid-disintegration tablet should be palatable to the patient. When necessary, palatability of drugs can generally be enhanced through the application of existing technologies; for example, those that involve coating and/or microencapsulation or formulation means. Additionally, the rapid-disintegration tablet must have adequate hardness and resistance to resist chipping and abrasion during manufacture, packaging and handling without unduly increasing the disintegration time upon administration to a patient.
There is a need for a highly compactable, rapidly dispersing tablet matrix containing one or more pharmaceutically active compounds that may be directly compressed to form rapidly dispersing tablets with practical hardness and resistance to chipping and abrasion. The primary challenge in developing tablets capable of rapid dispersion is the achievement of palatability and adequate robustness without compromising disintegration times. As such, there is a need for tablets that overcome such a challenge.
There also is a need to design a rapidly disintegrating tablet not only for an immediate release pattern but also for a modified-release model and others. Protective functional coatings, i.e., enteric or sustained-release coating, are usually intended to release the biologically active ingredient(s) at a certain part of the gastrointestinal (GI) tract or over a longer period of time after administration. In the case where active-loaded and membrane-coated beads or pellets are to be compressed into tablets, it is critical that the integrity of the functional coatings are maintained during compression.
Accordingly, there is a need for tablets that comprise very small cushioning components, which are particularly useful in the manufacture of dosage forms such as fast-disintegrating tablets which must be capable of being compressed yet retain disintegration rates and dose uniformity and robustness.
In sum, there is an overall need in the art for greater understanding of more efficient methods for preparing and utilizing solid dosage forms which comprise cushioning components which allow for compression of a tablet dosage form using conventional manufacturing equipment.
Citation of any reference in Section 2 of this application is not an admission that the reference is prior art to the application.